The Prion-like Domain in the Exomer-Dependent Cargo Pin2 Serves as a trans-Golgi Retention Motif

Prion and prion-like domains (PLDs) are found in many proteins throughout the animal kingdom. We found that the PLD in the S. cerevisiae exomer-dependent cargo protein Pin2 is involved in the regulation of protein transport and localization. The domain serves as a Pin2 retention signal in the trans-Golgi network (TGN). Pin2 is localized in a polarized fashion at the plasma membrane of the bud early in the cell cycle and the bud neck at cytokinesis. This polarized localization is dependent on both exo- and endocytosis. Upon environmental stress, Pin2 is rapidly endocytosed, and the PLD aggregates and causes sequestration of Pin2. The aggregation of Pin2 is reversible upon stress removal and Pin2 is rapidly re-exported to the plasma membrane. Altogether, these data uncover a role for PLDs as protein localization elements. [Display omitted] •Prion-like domains can be trans-Golgi network retention signals•PLDs can reversibly shift the equilibrium of protein distribution•PLDs may act as stress-response elements•Exomer-dependent cargoes need tightly regulated endo- and exocytosis for localization Prion-like domains (PLDs) occur in 0.3%–2.5% of cellular proteins, depending on the organism. Despite their relative abundance, the function of PLDs remains unclear. Now, Spang et al. show that a PLD can regulate trafficking/retention of a protein. The Pin2 PLD regulates protein distribution between the trans-Golgi network (TGN) and plasma membrane. Under stress, the PLD causes TGN sequestration of Pin2. Stress release causes rapid export of Pin2 to the plasma membrane.